Abstract CD8 T lymphocytes are the major mechanism by which the immune system eliminates cancers and virally infected cells. CD8 T cells detect these abnormal targets by recognizing immunogenic (e.g. viral or mutant) peptides displayed on MHC I molecules. Cancers and viruses can evade immune control and elimination by inhibiting MHC I antigen presentation, making them harder to detect, and/or by expressing molecules, such as PDL1, that inhibit attacking T cells. Therefore, it is important to understand the mechanisms by which tumors dysregulate these processes, how this affects cancer progression and immunotherapy, and how to reverse the immune evasion to improve outcomes - these are the overall goals of this proposal. Our proposal is based on our discovery in an unbiased forward genetic screen, of a transcription factor, IRF2, that unexpectedly is a positive regulator of MHC I antigen presentation and a negative regulator of PDL1 (CD274) expression. Our first aim will test the hypotheses that loss of expression of IRF2 is one of the ways that cancers escape immune surveillance and control to progress and that this is associated with worse clinical outcomes. Our second aim will test the hypotheses that the loss of IRF2 impairs the success of immunotherapy and that IRF2 will provide a much-needed biomarker to identify patients who would benefit, or not, from immunotherapy. The rational for this hypothesis is that the reduction in MHC I antigen presentation caused by loss of IRF2, will impair the ability of CD8 T cell responses that are invigorated by checkpoint blockade to find and kill their cancer targets. Our third aim hypothesizes that the loss of IRF2 expression is due to epigenetic silencing. Our goal is to determine the underlying mechanism for loss of IRF2 expression and to develop approaches to reverse the immune evasion caused by the loss of IRF2 that can be translated into future clinical trials. Our experimental approaches will use IRF2 gain of function and loss of function models, together with humanized and IRF2 KO mice to define the role of IRF2 in tumor immune evasion and responsiveness to immunotherapy with checkpoint blockade for both human and mouse cancers (Melanoma, NSCLC, & MCA sarcomas). We will translate these findings into human cancer patients, evaluating whether IRF2 is a biomarker that can predict clinical course and/or responsiveness to immunotherapy. Support for our hypotheses and feasibility of the proposed experiments are supported by strong preliminary data. Finally, we will use bioinformatics, seq techniques, inhibitors and cytokines to elucidate how IRF2 expression is lost and how to circumvent this loss for therapy.